Project Summary/Abstract Because of the graft vs leukemia effect (GVL), allogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative therapy for high risk leukemia and myelodysplasia in adults. However, the promise of HSCT is severely limited by graft versus host disease (GVHD). Acute graft-versus-host disease (aGVHD) is a principal contributor to transplant related mortality (TRM), and develops in approximately 60-80% of recipients receiving unrelated donor hematopoietic stem cell transplantation (HSCT) despite standard immunosuppressive prophylaxis. Thus, novel GVHD prophylaxis treatments which successfully attenuate aGVHD and related complications such as infection are urgently needed. CD24Fc has a novel mechanism of action that specifically targets the processes initiating GvHD, which is being developed for use in disease prophylaxis. CD24Fc has been demonstrated to be safe in healthy human subjects in a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT02650895) and the current study, a multi-center Phase II clinical trial, aims to provide the first toxicity/safety, pharmacokinetics, pharmacodynamics and biological activity data for CD24Fc in patients with hematological malignancies receiving allogeneic HSCT. The clinical trial has three primary objectives addressed by two different phases: Phase IIa will determine the safety and tolerability of CD24Fc in a single ascending dose-escalation study, and define the recommended Phase II dose (or Maximum Tolerated Dose) for prophylaxis of GVHD in a large Phase IIb expansion trial; Phase IIb will assess the in-human activity of CD24Fc in leukemia and myeloid dysplasia syndrome patients receiving HSCT; and both Phases will assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of CD24Fc in patients receiving HSCT. The ongoing Phase IIa portion of the trial (ClinicalTrials.gov Identifier: NCT02663622) is a randomized double blind single ascending dose trial comprised of 3 dosing cohorts of 8 patients (3:1 treatment:placebo), for a total planned enrollment of 24 subjects. CD24Fc is administered to patients on a background of standard of care prophylaxis comprising a calcineurin inhibitor and methotrexate to maximize patient safety. To date we have enrolled 6 patients in the Phase IIa trial with no drug related SAEs or DLTs. In addition, we propose an adaptive trial design that allows transition to the Phase IIb trial should our Phase IIa data demonstrate safety based on an interim analysis for all patients at 100 days, rather than waiting until the data on the secondary endpoints at one year. The planned Phase IIb study will involve a randomized, double blind, component where subjects will receive either standard GVHD prophylaxis with CD24Fc at the RP2D determined in Phase IIa (Arm A) versus standard GVHD prophylaxis with placebo (Arm B), with a planned enrollment of 90 patients per arm. This portion of the study will evaluate whether combining CD24Fc with standard prophylaxis provides evidence of clinical efficacy in the prevention of acute GVHD. With 180 patients (90 per arm), and assuming a Type I (alpha) error rate of 5%, there will be 80% power to detect a reduction in the primary endpoint of GVHD incidence at day 100 from 50% to 30%. The use of a randomized phase IIb design is felt to be highly necessary given historical variability in GVHD incidence, differences in GVHD grading and reporting, selection biases, heterogeneity among HCT populations, and other confounding variables such as ongoing changes in HCT supportive treatment. Furthermore, in the HCT field single arm phase II trials have consistently not been predictive of benefit in definitive phase III trials. The ultimate goal of this research project is to further the clinical development of a novel drug candidate, CD24Fc, and demonstrate therapeutic efficacy through a Phase IIb trial for the prophylactic treatment of aGVHD in leukemia patients undergoing allogeneic myeloablative HSCT. GVHD is an established orphan drug indication and OncoImmune, Inc. has obtained orphan drug designation for CD24Fc in both the US (orphan drug designation 15-4789) and the EU for the prevention of GvHD. Therefore, the project is clearly aligned with the mission of the FDA's Orphan Products Development (OPD) grant program to support the clinical development of products for use in rare diseases or conditions where no current therapy exists or where the proposed product will be superior to the existing therapy.